Neutrophil-derived reactive oxygen species promote tumor colonization

A single-nucleotide polymorphism of neutrophil cytosolic factor 1 (Ncf1), leading to an impaired generation of reactive oxygen species (ROS), is a causative genetic factor for autoimmune disease. To study a possible tumor protection effect by the Ncf1 mutation in a manner dependent on cell types, we used experimental mouse models of lung colonization assay by B16F10 melanoma cells. We observed fewer tumor foci in Ncf1 mutant mice, irrespective of αβT, γδT, B-cell deficiencies, or of a functional Ncf1 expression in CD68-positive monocytes/macrophages. The susceptibility to tumor colonization was restored by the human S100A8 (MRP8) promoter directing a functional Ncf1 expression to granulocytes. This effect was associated with an increase of both ROS and interleukin 1 beta (IL-1β) production from lung neutrophils. Moreover, neutrophil depletion by anti-Ly6G antibodies increased tumor colonization in wild type but failed in the Ncf1 mutant mice. In conclusion, tumor colonization is counteracted by ROS-activated and IL-1β-secreting tissue neutrophils.

Neutrophil Cytosolic Factor-1 Genotyping in Acne Vulgaris

Acne vulgaris (AV) is a very common inflammatory dermatosis. It has a complex pathogenesis in which oxidative stress plays an important role. Neutrophil cytosolic factor (NCF)-1 gene encodes for NCF1 protein which shares in reactive oxygen species (ROS) production. Copy number variation (CNV) is a type of genetic variance in which gene copies are duplicated or deleted. The current work aimed to detect the association between NCF1 CNV and NCF-1 genotypes and AV to explore their possible role in increased disease risk or influencing its clinical presentation. Twenty-five cases with AV and 25 age- and gender-matched healthy volunteers were selected. NCF1 CNV and genotypes were determined using quantitative real-time polymerase chain reaction. NCF1 copy number was significantly increased in patients compared to the control group (p = 0.02). Higher copy number increased the risk of occurrence of AV by about 4-fold. The NCF1 genotype was more prevalent in patients (72%) compared to NCF1B (24%) and NCF1C (4%) variants, while NCF1B and NCF1C variants (68%) were more prevalent in the control group. The NCF1B genotype decreased the risk of occurrence of AV by 0.2-fold. NCF1 was significantly associated with cases more than controls (p = 0.005). It increased the risk of occurrence of acne by 5.4-fold. There was significant association between NCF1 copy number and disease duration where higher number was associated with long disease duration (p = 0.03). Higher copy number was also associated with the NCF1 genotype (p = 0.01). This study suggests that increased copy number of NCF1 gene may be a predisposing factor for AV development. However, the presence of NCF1B and NCF1C variants lowers ROS production and subsequently decreases the risk of development of AV.

Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

Upregulation of glutaminase 2 and neutrophil cytosolic factor 2 is associated with the poor prognosis of glioblastoma

Background: This study aimed to identify glioblastoma prognosis-associated genes with potential diagnosis or prognosis values using integrated bioinformatics analysis. Results: In total, 1831 differentially expressed genes (DEGs) between the glioblastoma and control samples were identified and were clustered into seven weighed gene co-expression network analysis (WGCNA) modules. These DEGs were associated with different functional categories and pathways. Nine prognosis-associated DEGs (including glutaminase 2 [ GLS2] and neutrophil cytosolic factor 2 [ NCF2]) were identified, and the higher expression levels of GLS2 and NCF2 genes were associated with the poor prognosis of glioblastoma in ‘The Cancer Genome Atlas’ cohort and a clinical cohort. Conclusion: These results showed that the two genes play novel roles in the etiological and development of glioblastoma.